Tissue ischemia, defined as insufficient blood flow for providing oxygen and nutrients, is a serious clinical problem associated with aging, diabetes, hypercholesterolemia, and obesity. Ischemia results from progressive functional decline of large and small blood vessels and the consequences are debilitating and often fatal. The specific objectives of the proposed research plan are to identify effective, mechanistically characterized strategies, employing natural products, for overcoming current barriers to alleviation of ischemia. The specific aims are: (Aim 1a) Investigate oral administration of aqueous extracts of Barleria lupulina (AE-BL) for remedying ischemia-driven dysfunctional angiogenesis in mouse models, and define benefits for tissue oxygenation and survival; (Aim 1b) Define cellular and molecular mechanisms; (Aim 2a) Identify the individual components constituting the full activity of un-fractionated AE-BL, which stabilize the endothelial cell (EC) cytoskeleton and EC-EC junctions; (Aim 2b) Indentify combinations of purified components that remedy dysfunctional, ischemia-driven angiogenesis similarly to the un-fractionated extract. The specific vascular improvements (e.g., vessel architecture, lumen formation, network integration, barrier integrity, blood flow) provided by oral administration of AE-BL, and the resulting improvement in tissue oxygenation and tissue survival will be defined in mouse models of ischemia-driven angiogenesis. EC signaling pathways and cytoskeleton-regulating mechanisms through which AE-BL remedies dysfunctional vascular morphogenesis and thereby improves angiogenesis will be defined with ECs in vitro. These in vitro assays also will be employed to identify purified components of AE-BL with important bioactivity and to identify combinations of purified components comprising bioactivity similar to un-fractionated AE-BL. Thus, the proposed research plan is designed to illustrate a new strategy for remedying dysfunctional angiogenesis and alleviating tissue ischemia with un-fractionated AE-BL and also to identify specific compounds that embody this important biological activity. PUBLIC HEALTH RELEVANCE: Ischemic disease, caused by insufficient blood flow, is a serious clinical problem associated with aging, diabetes, hypercholesterolemia, and obesity. Ischemic disease results from progressive functional decline of blood vessels and the consequences are debilitating and often fatal. The objectives of the proposed research are to identify new effective strategies, using natural products, for successfully treating this disease.